Aggressive brain tumors can originate from a range of nervous system cells

Scientists have long believed that glioblastoma multiforme
(GBM), the most aggressive type of primary brain tumors, begins in glial
cells that make up supportive tissue in the brain or in neural stem cells.
In a paper published in Science, however, Salk researchers reported that
the tumors can originate from other types of differentiated cells in the nervous
system, including cortical neurons.

"One of the reasons for the lack of clinical advances in GBM has been
the insufficient understanding of the underlying mechanisms by which
these tumors originate and progress," says Inder Verma, a professor in
Salk's Laboratory of Genetics and the holder of the Irwin and Joan Jacobs
Chair in Exemplary Life Science.

To better understand this process, Verma's team harnessed the power of
modified viruses, called lentiviruses, to disable powerful tumor suppressor
genes in mice that regulate the growth of cells and inhibit the development
of tumors. With these tumor suppressors deactivated, cancerous cells
are given free rein to grow out of control. The modified viruses target two
genes—neurofibromatosis 1 (NF1) and p53—that, when mutated, are
implicated in severe gliomas like GBM. Using sophisticated analytical
techniques, they discovered that neurons genetically converted by the
lentiviruses are capable of forming malignant gliomas.

"Our findings," says lead author Dinorah Friedmann-Morvinski, a
postdoctoral researcher in the Laboratory of Genetics, "suggest that, when
two critical genes—NF1 and p53—are disabled, mature, differentiated cells
acquire the capacity to reprogram [dedifferentiate] to a neuroprogenitor
cell-like state, which can not only maintain their plasticity, but also give rise
to the variety of cells observed in malignant gliomas."

GBM is one of the most devastating brain tumors that can affect humans.
Despite progress in genetic analysis and classification, the prognosis
of these tumors remains poor, with most patients dying within one to two
years of diagnosis. The Salk researchers' findings suggest potential new
targets to treat these deadly cancers.

"Our results offer an explanation of recurrence of gliomas following
treatment," says Verma, "because any tumor cell that is not eradicated can
continue to proliferate and induce tumor formation, thereby perpetuating
the cycle of continuous cell replication to form malignant gliomas."